The present invention relates in general to recombinant virus strains, live viral vaccines, methods for making the strains and vaccines, and methods for immunizing a host against a virus. More specifically, the present invention relates to recombinant herpesvirus strains, live viral vaccines incorporating such strains, methods for making such strains and vaccines, and methods for immunizing a human host against herpes simplex virus using the vaccines wherein a vaccinal viral DNA does not encode an active ICP34.5 gene product, such as a herpesvirus having a deletion or a stop codon in reading frame within a coding region in all copies of the ICP34.5 gene.
Viruses may cause infected cells to produce specific proteins. These proteins interact with each other and with cellular proteins and with viral nucleic acids to cause viral progeny to be made, to destroy the infected cell and to spread infection to previously noninfected cells. Some of these proteins also stimulate a host immune response, which may permit the viruses encoding them to be useful as a component of a viral vaccine.
Herpes simplex virus (HSV) is a relatively common human pathogen which can cause fatal disease in the young or immunosuppressed.
There are two distinct serotypes, herpes simplex virus type 1 ("HSV-1") and herpes simplex virus type 2 ("HSV-2"), respectively associated with fever blisters and genital lesions. HSV-1 and HSV-2 are related immunologically, but most of their proteins carry distinguishing characteristics which allow them to be differentiated. See, Morse et al., J. Virol., 26(2), 389-410 (1978), the disclosure of which is incorporated herein by reference.
HSV is characterized by the ability to establish latent infections in the central nervous system ("CNS") of its host, specifically the neural ganglia [Stevens et al., J. Exp. Medicine, 133, 19-38 (1971)). This tropism for the CNS may result in encephalitis [Whitley, Virology, 2nd ed., Fields et al., eds., Raven Press, New York, 1843-1887 (1990)].
Several regions of the HSV genome may relate to viral neurovirulence. These regions include those containing the thymidine kinase gene [Field et al., J. Hygiene, 81, 267-277 (1978)] the DNA polymerase gene [Larder et al., J. Gen. Virol., 67 2501-2506 (1986)], sequences within the internal repeats (Thompson et al., J. Virol., 55(2), 504-508 (1985); Meignier et al., J. Infect. Diseases, 158(3), 602-614 (1988), and sequences between map units ("mu") 0.25 and 0.53 [Thompson et al., J. Virol., 58, 203-211 (1986)]. A neural-specific, latency-associated transcript (LAT) in the long repeats may also be of interest, although there is no demonstrated function for the transcript thereof.
A virus strain useful in a vaccine against HSV-1 and HSV-2 may be avirulent, stable (i.e., does not revert to the virulent state), provide demonstrated immunity to massive challenges of wild type strains of both HSV-1 and HSV-2, have low pathogenicity, and be incapable of transforming host cells. It may be desirable for the vaccinal virus to disappear, or capable of reactivation, after immunization of a host, but in some cases it may be desirable for the virus to remain in a latent form in the host. This is best accomplished by a virus which contains only a small alteration in the genomic structure, thereby preserving the ability to replicate well outside the host while maintaining normal expression of immunity-inducing viral components.
Therefore, it is useful to obtain a stable, non-transforming live viral vaccine which either does not establish latent infections or which cannot be reactivated from a latent state, and which is effective against a herpes simplex virus.